The present invention relates to chemical compounds, pharmaceutical compositions, and to a method of treatment employing the compounds and compositions. More particularly, the present invention is concerned with certain 1,2,5,6-tetrahydro-1-substituted 3- or 4-pyridine oximes, to pharmaceutical compositions containing these compounds, and to a pharmaceutical method of treatment.
Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well accepted. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least ten percent of persons over sixty years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
Many of the symptoms of cognitive disorders, especially impaired memory, are associated with decreased acetylcholine synthesis and the impairment of cholinoreceptive neurons. In the hippocampus and cerebral cortex of patients suffering from primary degenerative dementia for example, the level of the enzyme choline acetyltransferase (CAT) can be reduced by as much as ninety percent. (See Davies et al., The Lancet, 1976 (Vol. 2): 1403; Perry et al., J. Neurol. Sci., 34: 247-265 (1977); and White et al., The Lancet, 1977 (Vol. 1): 668-670).
Since CAT catalyzes the synthesis of acetylcholine from its precursors choline and acetyl coenzyme A, the loss of CAT reflects the loss of cholinergic, or acetylcholine-releasing, nerve endings in the hippocampus and cerebral cortex. There is abundant evidence that cholinergic terminals in the hippocampus are critically important for memory formation.
The cholinergic hypothesis suggests that drugs which restore acetylcholine levels or which mimic the action of acetylcholine (i.e. are cholinomimetic) are effective in correcting this deficit in neurotransmitter chemical and provide treatment of the memory impairment symptom of cerebral insufficiency. Considerable biochemical, pharmacological, and electrophysiological evidence supports the hypothesis that deficits in the cholinergic system underlie geriatric cognitive dysfunction. (See C. Peterson and G. E. Gibson, Neurobiol. Aging, 4: 25-30 (1983)). Aged humans and non-human primates with decreased cognition show improved memory when they are treated, for example, with acetylcholinesterase inhibitors such as physostigmine. These agents increase the available supply of synaptic acetylcholine by inhibiting its hydrolysis.
Aminopyridines such as 3,4-diaminopyridine ameliorate age-related cognitive deficits by increasing the release of acetylcholine from presynaptic nerve terminals, thus increasing synaptic acetylcholine. (See H. P. Davis et al., Exp. Aging Res., 9: 211-214 (1983)).
It has been known for some time that the natural alkaloid, muscarine, has the ability to act relatively selectively at autonomic effector cells to produce qualitatively the same effects as acetylcholine. Two related alkaloids, pilocarpine and arecoline, have the same principal sites of action as muscarine and acetylcholine and are thus classified as having "muscarinic" action. Although these naturally occurring alkaloids are of great value as pharmacological tools, present clinical use is largely restricted to the use of pilocarpine as a miotic agent.
Arecoline (the methyl ester of 1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxylic acid) is the chief alkaloid found in betel nuts (Areca catechu). Betel nuts have been chewed by natives of the East Indies since early times as a euphoretic. The present pharmaceutical utility of arecoline, however, has been limited to its use as a veterinary anthelmintic agent.
Recently it has been demonstrated that arecoline is effective in ameliorating some of the symptoms of cognitive disorders in patients clinically diagnosed as having presenile primary degenerative dementia. Significant improvement was observed in a test of picture recognition after administration of arecoline to patients in a double blind study. (See Christie et al., Brit. J. Psychiatry, 138: 46-50 (1981)).
Certain 3- or 4-ketoximes of 1-(lower alkyl)-1,2,5,6-tetrahydropyridines in which the oxygen is unsubstituted are disclosed in U.S. Pat. No. 3,004,979, having utility as parasympathomimetic agents acting on non-striated muscle.
Regarding analgesia, the literature indicates that acetylcholine and muscarine agonists possess antinociceptive activity (see T. T. Chau et al., J. Pharmacol. Exp. Ther., 222: 612-666 (1982),; W. L. Dewey et al., Life Sci., 17: 9-10 (1975); and N. W. Pedigo et al., Neurosci. Lett., 26: 85-90 (1981) and references cited therein).
The classification and nomenclature of phencyclidine and sigma receptor sites has been reviewed (Trends Neurosci. 1987, 10: 444-446). See also Clin. Neuropharmacol. 1988, 11: 105. The structural determinants of sigma receptor affinity have been described (Mol. Pharmacol. 1987, 32: 772-784). We have found that a new structural class of chemical compounds, e.g. tetrahydropyridine oximes, have unexpectedly high affinity for the sigma site.
Sigma receptor agonists may serve to modulate the actions of a variety of transmitters (Eur. J. Pharmacol. 1988, 149: 399-400).
1,3-Disubstituted-guanidine sigma receptor ligands are useful in the diagnosis and treatment of hallucination associated psychotic mental illness (e.g., schizophrenia) and chronic mental depression (U.S. Pat. No. 4,709,094, Trends Neurosci. 1988, 11: 37-40.
Since haloperidol and many other antipsychotic drugs exhibit an affinity for sigma receptors which is at least equal to its affinity for dopamine receptors, these data raise the further possibility that sigma receptors are involved in the motor side effects of antipsychotic drugs (Neurology 1988, 38: 961-965).
The sigma site plays a role in immune system functioning, for example, as evidenced by steroid binding at sigma receptors and the link between endocrine, nervous, and immune systems (Science 1988, 240: 219-221). See also Eur. J. Pharmacol. 1988; 148: 467-470. Additionally, sigma ligands prevent the proliferative response of T lymphocytes by lowering IL2 production (Biochem. Pharmacol. 1987, 36: 3929-3936). The aforementioned articles suggest activity as antiinflammatories or immunosuppressants.